The available means for delivering pharmaceutical and therapeutic agents to mammals often are severely limited by chemical or physical barriers or both, which are imposed by the body. For example, oral delivery of many biologically-active agents would be the route of choice if not for the presence of chemical and physicochemical barriers such as extreme pH in the gut, exposure to powerful digestive enzymes, and impermeability of gastrointestinal membranes to the active ingredient. Among the numerous pharmacological agents which are known to be unsuitable for oral administration are biologically active peptides and proteins, such as insulin. These agents are rapidly destroyed in the gut by acid hydrolysis and/or by proteolytic enzymes.
Much research has been devoted to developing effective oral drug delivery methods and systems for these vulnerable pharmacological agents. The proposed solutions have included:
(a) co-administration of adjuvants (such as resorcinols and non-ionic surfactants polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether to increase the permeability of the intestinal walls; and PA1 (b) co-administration of enzymatic inhibitors, such as pancreatic trypsin inhibitor, diisopropylfluorophosphate (DFF) and trasylol to avoid enzymatic degradation. PA1 (a) inherent toxicity when employed in effective amounts; or PA1 (b) failure to protect the active ingredient or promote its absorption; or PA1 (c) adverse interaction with the drug. PA1 (a) poor stability; PA1 (b) inadequate shelf life; PA1 (c) limited to low MW (&lt;30,000) cargoes; PA1 (d) difficulty in manufacturing; PA1 (e) adverse interactions with cargoes.
The use of such substances, in drug delivery systems, is limited however either because of their:
Liposomes as drug delivery systems have also been described. They provide a layer of lipid around the encapsulated pharmacological agent. The use of liposomes containing heparin is disclosed in U.S. Pat. No. 4,239,754 and several studies have been directed to the use of liposomes containing insulin; e.g., Patel et al. (1976) FEBS Letters Vol. 62, page 60 and Hashimoto et al. (1979) Endocrinol. Japan, Vol. 26, page 337. The use of liposomes, however, is still in the development stage and there are continuing problems, including:
More recently, artificial amino acid polymers or proteinoids, forming microspheres, have been described for encapsulating pharmaceuticals. For example, U.S. Pat. No. 4,925,673 (the '673 patent), the disclosure of which is hereby incorporated by reference in its entirety, describes such microsphere constructs as well as methods for their preparation and use. The microspheres of the '673 patent are useful for encapsulating a number of active agents, however there is a need in the art for microsphere carriers that can encapsulate a broader range of active agents such as lipophilic drugs.
Additionally, the method employed in the '673 patent for preparing proteinoids results in a complex mixture of high molecular weight (MW) (&gt;1000 daltons) and low MW (.ltoreq.1000 daltons) peptide-like polymers which are difficult to separate. Moreover, small amounts of the low MW microsphere-forming proteinoids are obtained. Thus, an improved method of preparing low molecular weight sphere-forming proteinoids is also desired.